MEDI5752 in Patients With Mature Tertiary Lymphoid Structures Solid Tumors.

Multicentric, prospective, multi-indication, single-treatment arm, open-label phase II trial assessing the efficacy of MEDI5752.

Patients with mature tertiary lymphoid structures advanced solid tumors will be included in two independent cohorts:

• Cohort A: patients with TLS+ IO-naïve solid tumor (miscellaneous)
• Cohort B: patients with TLS+ PD1/PDL1-experienced solid tumor (miscellaneous) Each cohort will rely on a two-stage three-outcome design as described in Sargent et al.

Inclusion criteria

• Histologically confirmed solid tumor
• IO-naïve patients (cohort A) OR patients with secondary resistance to PD1/PDL1 inhibitors (cohort B),
• Patients in cohort B:

• have to be diagnosed previously treated with PD-L1/PD-1 inhibitors (investigational or approved),
• must have experienced initial clinical benefit (stable disease or better) from checkpoint inhibitor therapy for at least 4 months in which there was at least one interval scan prior to 4 months demonstrating no progression of disease.
• Presence of mature tertiary lymphoid structures (TLS) by IHC as described in protocol section 3.2.4. Except if presence of TLS has been already confirmed by Biopathological platform at Bergonié Institute, presence of TLS should be confirmed by central review based on FFPE tumor tissue sample,
• Advanced unresectable or metastatic solid disease,
• Measurable disease according to RECIST v1.1
• At least one tumor site that can be biopsied for research purpose,
• Age ≥ 18 years,
• Body weight > 35 kg,
• ECOG ≤ 1,
• Life expectancy > 3 months,
• Adequate hematological, renal, metabolic, hepatic and cardiac functions:
• Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment. Note that no more than three lines of systemic treatment for metastatic disease are allowed and that patients with oncogenic addiction must have progressed on prior approved regimens),
• Recovery to grade ≤ 1 from any adverse event derived from previous treatment (excluding alopecia of any grade (according to the NCI-CTCAE, version 5.0),
• Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to study entry.
• Women and men must agree to use at least one medically highly effective method of contraception from screening, throughout the treatment period
• Voluntary signed and dated written informed consents prior to any specific study procedure,
• Patients with a social security in compliance with the French law.

Exclusion criteria

• Any anticancer treatment within 21 days or 5 half-lives (whichever is shorter) prior to start of study treatment,
• Whole brain radiotherapy within 14 days prior to start of study treatment,
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.
• Stereotactic radiosurgery within 7 days prior to start of study treatment,
• Major surgery within 4 weeks prior to start of study treatment or still recovering from prior surgery
• Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding,
• History of or concurrent serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study or confounds the ability to interpret data from the study
• Prior or concurrent malignant disease
• Any prior Grade ≥ 3 imAE while receiving immunotherapy or any unresolved imAE > Grade 1
• For subjects who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4 : Subject must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy, must not have experienced a ≥ grade 3 imAE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy, must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, must not have experienced recurrence of an AE if rechallenged, and must not currently require maintenance doses of > 10 mg prednisone or equivalent per day
• Symptomatic or actively progressing central nervous system metastases.
• History of leptomeningeal disease or cord compression
• Uncontrolled or symptomatic hypercalcemia
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, cardiomyopathy of any etiology, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, history of myocardial infarction within the past 12 months, cardiac arrhythmia, ILD, serious chronic gastrointestinal conditions associated with diarrhea,
• Cerebrovascular accident within 6 months prior to enrolment,
• Any concurrent chemotherapy, radiotherapy, investigational, biologic, or hormonal therapy for cancer treatment.
• Active or history of autoimmune disease immune deficiency or inflammatory disorders, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, sarcoidosis syndrome, rheumatoid arthritis, hypophysitis, uveitis, inflammatory bowel disease, diverticulitis antiphospholipid antibody syndrome, Wegener granulomatosis, Graves'disease, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis,
• History of idiopathic pulmonary fibrosis, organizing pneumonia drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening CT scan.
• Evidence of the following infections: active infection including tuberculosis, HIV, active hepatitis B or C or A
• Any contraindication to biopsy for the research,
• Participation to a study involving a medical or therapeutic intervention in the last 30 days,
• Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons,
• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia,
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment.
• Prior allogeneic stem cell or solid organ transplantation,
• Treatment with a live, attenuated vaccine within 30 days prior to initiation of study treatment
• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic Immunosuppressive medication during study treatment,
• History of severe allergic anaphylactic reaction to chimeric or humanized antibodies or fusion proteins,
• Known hypersensitivity to Chinese hamster ovary cell products, to any component of the MEDI5752 formulation or to any human globulin therapy.